Prostacyclin (or PGI2) is a member of the family of lipid molecules known as eicosanoids. It is a potent vasodilator, antiproliferative, anti-thrombotic agent that mediates its effects as an agonist of the IP receptor. The IP receptor is a G-protein coupled receptor that, upon activation by prostacyclin, stimulates the formation of cyclic adenosine monophosphate (cAMP). Prostacyclin counteracts the vasoconstrictor and pro-thrombotic activity of endothelin.
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy leading to right ventricular hypertrophy. Exogenous administration of an agonist of the IP receptor has become an important strategy in the treatment of PAH. (See, e.g., Tuder et al., Am. J. Respir. Crit. Care. Med., 1999, 159: 1925-1932; Humbert et al, J. Am. Coll. Cardiol., 2004, 43:13S-24S; Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11:609-619; McLaughlin et al, Circulation, 2006, 114:1417-1431; Rosenkranz, Olin. Res. Cardiol., 2007, 96:527-541; Driscoll et al, Expert Opin. Pharmacother., 2008, 9:85-81.).
The prostacyclin analogue epoprostenol (flolan) is at least as effective as transplantation in terms of survival. Despite this, it is not used as frontline therapy due to significant tolerability, convenience and cost issues. Instead, patients with PAH are often treated first with either endothelin receptor antagonists (e.g. bosentan) and/or PDE5 inhibitors (e.g. sildenafil), which are better tolerated but can have limited efficacy. Prostacyclin analogues are used mainly as add-on treatment as severity of the disease progresses and tolerability and convenience become less of an issue.
Two key issues prevent current prostacyclin analogues being used as frontline therapy in PAH. Firstly, they are very unstable with an extremely short half-life, meaning they must be constantly infused via an in-dwelling intra venous (i.v.) catheter that is both inconvenient for the patient and also associated with a significant risk of infection and sepsis. Secondly, they are associated with significant side effects including nausea, jaw pain, headache and other side effects associated with systemic hypotension.
One solution to these issues is iloprost, which is available as a nebulized formulation that has reduced tolerability issues, but the short half life results in a 6-9 times daily dosing regime. More recently, researchers made efforts to generate stable, orally available IP receptor agonists. These ligands would improve patient convenience and compliance, but high levels of systemic drug is required to achieve pharmacodynamic effects in the lung; thus, possibly generating similar side effects to those observed with i.v. flolan.
The present invention describes stable, highly selective IP receptor agonists that are suitable for oral and inhaled delivery. The present invention offers a significant improvement over existing prostacyclin analogues and enables their use in less-severe patients. In addition, long term activation of the IP receptor has been shown to reverse remodeling associated with PAH; therefore, earlier intervention with the present invention may have significant effects on disease progression and potentially may show reversal.
In addition, pharmaceutical research has considerable interest in developing IP receptor agonists for the treatment of pulmonary fibrosis. IP deficient mice have been shown to be more susceptible to bleomycin-induced lung fibrosis than wild-type animals (Lovgren A K et al. (2006) Am J Physiol Lung Cell Mol Physiol. 291:L144-56), and the IP receptor agonist iloprost increases survival in bleomycin-treated mice (Zhu et al (2010) Respir Res. 11(1):34).
Furthermore, IP receptor signaling has been shown to exert beneficial effects in fibrotic conditions of various organs in animal models and in patients. Benefits of IP receptor agonist were shown for fibrosis of the heart, lung, skin, pancreas and liver, and in systemic sclerosis. (Gayraud M (2007) Joint Bone Spine. 74(1):e1-8; Hirata Y et al (2009) Biomed Pharmacother. 63(10):781-6; Kaneshige T et al (2007) J Vet Med Sci. 69(12):1271-6; Sahsivar M O et al (2009) Shock 32(5):498-502; Sato N et al (2010) Diabetes 59(4):1092-100; Shouval D S et al (2008) Clin Exp Rheumatol. 26(3 Suppl 49):S105-7; Spargias K et al (2009) Circulation. 120(18):1793-9; Stratton R et al (2001) J Clin Invest. 108(2):241-50; Takenaka M et al (2009) Prostaglandins Leukot Essent Fatty Acids. 80(5-6):263-7; Watanabe M et al (2009) Am J Nephrol. 30(1):1-11; Yano T et al (2005) Am J Pathol. 166(5):1333-42; Zardi E M et al (2007) Expert Opin Biol Ther. 7(6):785-90; Zardi E M et al (2006) In Vivo 20(3):377-80; Rehberger P et al (2009) Acta Derm Venereol. 89(3):245-9). Fibrotic conditions can occur in most organs secondary to chronic inflammation indications throughout the body and are likely to share common causes.
Therefore, antifibrotic agents such as IP receptor agonists of the present invention are of potential benefit in all indications that are associated with fibrotic tissue remodeling.
There is considerable, interest in developing agonists of the IP receptor for use in the treatment of other diseases, such as atherothrombosis, preeclampsia. It is highly desirable to develop a stable, inhaled agonists of the IP receptor, which may lead to improved management of PAH.
The invention pertains to the compounds, methods for using them, and uses thereof as described herein. Examples of compounds of the invention include the compounds according to any of Formula I, Ia, II or IIa, or a pharmaceutically acceptable salt thereof, and the compounds of the examples.
The invention therefore provides a compound of the Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein
A is N or CR′;
R′ is H, C1-C8 alkyl optionally substituted by one or more halogen atoms;
R1 is H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, OR′, —NR19R21, CN or C3-C7 cycloalkyl; or
R1 is —X—Y; or
R1 is —W—R7—X—Y; or
R1 is —S(O)2—W—X—Y; or
R1 is —S(O)2—W—R7—X—Y;
R2 is H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, OR′, —NR19R21, CN or C3-C7 cycloalkyl; or
R2 is —X—Y; or
R2 is —W—R7—X—Y; or
R2 is —S(O)2—W—X—Y;
R2 is —S(O)2—W—R7—X—Y;
wherein either R1 or R2 is —X—Y, —S(O)2—W—X—Y; or —S(O)2—W—R7—X—Y;
R2a is hydrogen; or
R2 and R2a taken together are oxo;
R3 is H, C1-C4 alkoxy, OH, —NR19R21CN, halogen, C3-C7 cycloalkyl or C1-C8 alkyl optionally substituted by one or more halogen atoms;
R4 is H, C1-C4 alkoxy, OH, —NR19R21CN, halogen, C3-C7 cycloalkyl or C1-C8 alkyl optionally substituted by one or more halogen atoms;
R5 is C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, OR′, —NR19R21, CN or C3-C7 cycloalkyl; C1-C8 alkoxy optionally substituted by one or more halogen atoms; C6-C14 aryl; —(C0-C4 alkyl)-4 to 14 membered heteroaryl, or —(C0-C4 alkyl)-3 to 14 membered heterocyclyl wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl are each optionally substituted by one or more Z substituents;
R6 is C6-C14 aryl; —(C0-C4 alkyl)-4 to 14 membered heteroaryl, —(C0-C4 alkyl)-3 to 14 membered heterocyclyl wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl are each optionally substituted by one or more Z substituents;
W is C1-C8 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
X is C1-C8 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
Y is carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or —CONH—S(O)q—Rx, wherein Rx is —C1-C4 alkyl or —NR19R21;
q is 0, 1 or 2;
R7 is a divalent moiety represented by —O—, —NHC(O)—, —CH2═CH2—, —C6-C14 aryl-D-; −3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O, S, NH or not present;
Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, C1-C6 alkoxy optionally substituted by one or more OH groups, C1-C6 alkoxy optionally substituted by one or more halogen, C1-C6 alkoxy optionally substituted by C1-C4 alkoxy, NR18(SO2)R21, (SO2)NR19R21, (SO2)R21, NR18C(O)R21, C(O)NR19R21, NR18C(O)NR19R21, NR18C(O)OR19, NR19R21, C(O)OR19, C(O)R19, SR19, OR19, oxo, CN, NO2, halogen or a 3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S;
R18 is independently H or C1-C6 alkyl;
R19 and R21 are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4 alkoxy-C1-C4 alkyl; (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; (C0-C4 alkyl)-3- to 14-membered heterocyclyl, the heterocyclyl including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C8 alkyl; (C0-C4 alkyl)-O-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; and (C0-C4 alkyl)-O-3- to 14-membered heterocyclyl, the heterocyclyl including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl or C(O)C1-C6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C1-C4 alkoxy, C(O)NH2, C(O)NHC1-C6 alkyl or C(O)N(C1-C6 alkyl)2; or
R19 and R21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclyl, the heterocyclyl including one or more further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclyl including one or more heteroatoms selected from N, O and S; S(O)2-aryl; S(O)2—C1-C6 alkyl; C1-C6 alkyl optionally substituted by one or more halogen atoms; C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy; and C(O)OC1-C6 alkyl, wherein the aryl and heterocyclyl substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.
Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.
In an embodiment of the invention as described anywhere herein, A is N.
In an embodiment of the invention as described anywhere herein, A is CR′.
In an embodiment of the invention as described anywhere herein, A is CR′, wherein R′ is H.
In an embodiment of the invention as described anywhere herein, wherein
R1 is H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, or OR′; or R1 is —X—Y; or R1 is —W—R7—X—Y; or R1 is —S(O)2—X—Y or R2 is —S(O)2—W—R7—X—Y;
R2 is H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, or OR′; R2 is —X—Y; or R2 is —W—R7—X—Y; or R2 is —S(O)2—X—Y; R2 is —S(O)2—W—R7—X—Y;
wherein either R1 or R2 is —X—Y, —S(O)2—W—X—Y; or —S(O)2—W—R7—X—Y;
W is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
X is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
Y is —C(O)OH, —C(O)ORx, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or —CONH—S(O)q—Rx, wherein Rx is —C1-C4 alkyl or —NR19R21; and
q is 2;
R′ is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
R7 is a divalent moiety represented by —C6-C14 aryl-D-; −3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O;
R19 and R21 are each independently H; C1-C8 alkyl.
In an embodiment of the invention as described anywhere herein, wherein
R1 is —X—Y; or —W—R7—X—Y;
R2 is H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, or OR′;
W is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
X is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
Y is —C(O)OH, —C(O)ORx, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or —CONH—S(O)q—Rx, wherein Rx is —C1-C4 alkyl or —NR19R21; and
q is 2;
R′ is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
R7 is a divalent moiety represented by —C6-C14 aryl-D-; −3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S,
wherein D is O;
R19 and R21 are each independently H; C1-C8 alkyl.
In an embodiment of the invention as described anywhere herein, wherein
R1 is —X—Y; or —W—R7—X—Y;
R2 is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
W is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
X is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
Y is —C(O)OH;
R7 is a divalent moiety represented by —C6-C14 aryl-D-; −3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O.
In an embodiment of the invention as described anywhere herein, wherein
R1 is C1-C4 alkyl optionally substituted by one or more halogen atoms, —(CH2)m—C(O)OR″, or —(CH2)m—R7—(CH2)n—C(O)OR″;
R2 is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
m is 1, 2, 3, 4, 5, 6, 7 or 8;
n is 0, 1, 2 or 3;
R″ is H or C1-C4 alkyl optionally substituted by one or more halogen atoms;
R7 is a divalent moiety represented by —C6-C14 aryl-D-; −3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O;
In an embodiment of the invention as described anywhere herein, wherein
R1 is —(CH2)m—C(O)OR″, or —(CH2), —R7—(CH2)n—C(O)OR″;
R2 is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
m is 1, 2, 3, 4, 5, 6, 7 or 8;
n is 0, 1, 2 or 3;
R″ is H or C1-C4 alkyl optionally substituted by one or more halogen atoms;
R7 is a divalent moiety represented by —C6-C14 aryl-D-; −3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O.
In an embodiment of the invention as described anywhere herein, wherein
R1 is —(CH2)m—C(O)OR″;
R2 is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
m is 1, 2, 3, 4, 5, 6, 7 or 8;
R″ is H or C1-C4 alkyl optionally substituted by one or more halogen atoms.
In an embodiment of the invention as described anywhere herein, wherein
R1 is —(CH2)m—C(O)OR″;
R2 is H;
R″ is H;
m is 4, 5 or 6.
In an embodiment of the invention as described anywhere herein, wherein

In an embodiment of the invention as described anywhere herein, wherein

In an embodiment of the invention as described anywhere herein, wherein
R3 is H, C1-C4 alkoxy, OH, —NR19R21, CN, halogen, C3-C7 cycloalkyl or C1-C4 alkyl optionally substituted by one or more halogen atoms;
R4 is H, C1-C4 alkoxy, OH, —NR19R21, CN, halogen, C3-C7 cycloalkyl or C1-C4 alkyl optionally substituted by one or more halogen atoms.
In an embodiment of the invention as described anywhere herein, wherein
R3 is H, C1-C4 alkoxy, OH, CN, halogen, C3-C7 cycloalkyl or C1-C4 alkyl optionally substituted by one or more halogen atoms;
R4 is H, C1-C4 alkoxy, OH, CN, halogen, C3-C7 cycloalkyl or C1-C4 alkyl optionally substituted by one or more halogen atoms.
In an embodiment of the invention as described anywhere herein, wherein
R3 is H, methoxy, OH, CN, halogen, cyclopropyl or methyl;
R4 is H, methoxy, OH, CN, halogen, cyclopropyl or methyl.
In an embodiment of the invention as described anywhere herein, wherein
R3 is H, OH, cyclopropyl or methyl;
R4 is H, OH, cyclopropyl or methyl.
In an embodiment of the invention as described anywhere herein, wherein
R3 is H, or OH;
R4 is H, or OH.
In an embodiment of the invention as described anywhere herein, wherein
R5 is C6-C14 aryl; —(C0-C4 alkyl)-4 to 14 membered heteroaryl, or —(C0-C4 alkyl)-3 to 14 membered heterocyclyl wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl are each optionally substituted by one or more Z substituents; and
R6 is C6-C14 aryl; —(C0-C4 alkyl)-4 to 14 membered heteroaryl, —(C0-C4 alkyl)-3 to 14 membered heterocyclyl wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl are each optionally substituted by one or more Z substituents.
In an embodiment of the invention as described anywhere herein, wherein
R5 is C6-C14 aryl; −5 to 6 membered heteroaryl, or -5 to 6 membered heterocyclyl wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl are each optionally substituted by one or more Z substituents; and
R6 is C6-C14 aryl; −5 to 6 membered heteroaryl, -5 to 6 membered heterocyclyl wherein the heteroaryl and heterocyclyl contain at least one heteroatom selected from N, O and S, wherein the aryl, heteroaryl and heterocyclyl are each optionally substituted by one or more Z substituents.
In an embodiment of the invention as described anywhere herein, wherein
R5 is phenyl; 2-pyridyl, 3-pyridyl, or 4-pyridyl, and
R6 is phenyl; 2-pyridyl, 3-pyridyl, or 4-pyridyl,
wherein the phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl are each optionally substituted by one or more Z substituents.
In an embodiment of the invention as described anywhere herein, wherein
R5 is phenyl optionally substituted by OH, C1-C4 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, NR19R21, C(O)OR19, C(O)R19, SR19, OR19, CN, NO2, or halogen; and
R6 is phenyl optionally substituted by OH, C1-C4 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, NR19R21, C(O)OR19, C(O)R19, SR19, OR19, CN, NO2, or halogen.
In an embodiment of the invention as described anywhere herein, wherein
R5 is phenyl optionally substituted by C1-C4 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy or halogen; and
R6 is phenyl optionally substituted by C1-C4 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy or halogen.
In an embodiment of the invention as described anywhere herein, wherein
R5 is phenyl optionally substituted by C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy or halogen; and
R6 is phenyl optionally substituted by C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy or halogen.
In an embodiment of the invention as described anywhere herein, wherein
R5 is phenyl optionally substituted by C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy or halogen; and
R6 is phenyl optionally substituted by C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy or halogen.
In an embodiment of the invention as described anywhere herein, wherein

Another embodiment of the invention as defined above provides compounds according to Formula II, represented by

In an embodiment of the invention as described in Formula II herein, A is N.
In an embodiment of the invention as described Formula II herein, A is CR′.
In an embodiment of the invention as described Formula II herein, A is CR′, wherein R′ is H.
In an embodiment of the invention as described Formula II herein, wherein
R1 is H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, or OR′; or R1 is —X—Y; or R1 is —W—R7—X—Y; or R1 is —S(O)2—X—Y or R2 is —S(O)2—W—R7—X—Y;
R2 is H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, or OR′; R2 is —X—Y; or R2 is —W—R7—X—Y; or R2 is —S(O)2—X—Y; R2 is —S(O)2—W—R7—X—Y;
wherein either R1 or R2 is —X—Y, —W—R7—X—Y, —S(O)2—W—X—Y; or —S(O)2—W—R7—X—Y;
W is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
X is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
Y is carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or —CONH—S(O)q—Rx, wherein Rx is —C1-C4 alkyl or —NR19R21; and
q is 2;
R′ is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
R7 is a divalent moiety represented by —C6-C14 aryl-D-; −3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O;
R19 and R21 are each independently H; C1-C8 alkyl.
In an embodiment of the invention as described Formula II herein, wherein
R1 is —X—Y; or —W—R7—X—Y;
R2 is H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkyl, OH, or OR′;
W is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
X is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
Y is —C(O)OH, —C(O)ORx, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or —CONH—S(O)q—Rx, wherein Rx is —C1-C4 alkyl or —NR19R21; and
q is 2;
p is 0, 1, 2, 3, or 4;
R′ is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
R7 is a divalent moiety represented by —C6-C14 aryl-D-; −3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O;
R19 and R21 are each independently H; C1-C8 alkyl.
In an embodiment of the invention as described Formula II herein, wherein
R1 is —X—Y; or —W—R7—X—Y;
R2 is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
W is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
X is C1-C6 alkylene optionally substituted by hydroxy, halogens or C1-C4 alkyl;
Y is —C(O)OH;
p is 0, 1, 2, 3, or 4;
R7 is a divalent moiety represented by —C6-C14 aryl-D-; −3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O.
In an embodiment of the invention as described Formula II herein, wherein
R1 is —(CH2), —C(O)OR″, or —(CH2), —R7—(CH2)n—C(O)OR″;
R2 is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
m is 1, 2, 3, 4, 5, 6, 7 or 8;
n is 0, 1, 2 or 3;
p is 0, 1, 2, 3, or 4;
R″ is H or C1-C4 alkyl optionally substituted by one or more halogen atoms;
R7 is a divalent moiety represented by —C6-C14 aryl-D-; −3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O;
In an embodiment of the invention as described Formula II herein, wherein
R1 is —(CH2), —C(O)OR″, or —(CH2), —R7—(CH2)n—C(O)OR″;
R2 is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
m is 1, 2, 3, 4, 5, 6, 7 or 8;
n is 0, 1, 2 or 3;
p is 0, 1, 2, 3, or 4;
R″ is H or C1-C4 alkyl optionally substituted by one or more halogen atoms;
R7 is a divalent moiety represented by —C6-C14 aryl-D-; −3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is O.
In an embodiment of the invention as described Formula II herein, wherein
R1 is —(CH2), —C(O)OR″;
R2 is H, C1-C4 alkyl optionally substituted by one or more halogen atoms;
m is 1, 2, 3, 4, 5, 6, 7 or 8;
p is 0, 1, 2, 3, or 4;
R″ is H or C1-C4 alkyl optionally substituted by one or more halogen atoms.
In an embodiment of the invention as described Formula II herein, wherein
R1 is —(CH2), —C(O)OR″;
R2 is H;
R″ is H;
m is 4, 5 or 6;
p is 0.
In an embodiment of the invention as described Formula II herein, wherein

p is 0 or 1.
In an embodiment of the invention as described Formula II herein, wherein

p is 0 or 1.
In an embodiment of the invention as described Formula II herein, wherein
R3 and R4 are independently H, OH, C1-C6 alkyl, C1-C4 alkoxy, cyano or halogen.
In an embodiment of the invention as described Formula II herein, wherein
R3 and R4 are independently H, OH, C1-C4alkyl, C1-C4alkoxy or halogen.
In an embodiment of the invention as described Formula II herein, wherein
R3 and R4 are independently H, OH, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, fluorine, bromine or chlorine.
In an embodiment of the invention as described anywhere herein, wherein
Z is independently OH, C6-aryl, O—C6-aryl, benzyl, O-benzyl, C1-C4 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, NR18(SO2)R21, (SO2)NR19R21, (SO2)R21, NR18C(O)R21, C(O)NR19R21, NR18C(O)NR19R21, NR18C(O)OR19, NR19R21, C(O)OR19, C(O)R19, SR19, OR19, oxo, CN, NO2, halogen or a 4 to 6 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S;
R18 is H or C1-C4 alkyl;
R19 and R21 are each independently H; C1-C4 alkyl; C3-C6 cycloalkyl; C1-C4 alkoxy-C1-C4 alkyl; (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected from C1-C4 alkyl, C1-C4 alkoxy and halogen; (C0-C4 alkyl)-4- to 6-membered heterocyclyl, the heterocyclyl including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C1-C4 alkyl and C(O)C1-C4 alkyl; (C0-C4 alkyl)-O-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen; and (C0-C4 alkyl)-O-3- to 14-membered heterocyclyl, the heterocyclyl including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl or C(O)C1-C6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C1-C4 alkoxy, C(O)NH2, C(O)NHC1-C6 alkyl or C(O)N(C1-C6 alky)2; or
R19 and R21 together with the nitrogen atom to which they attached form a 5- to 6-membered heterocyclyl, the heterocyclyl including one or more further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 6-membered heterocyclyl including one or more heteroatoms selected from N, O and S; S(O)2-aryl; S(O)2—C1-C6 alkyl; C1-C6 alkyl optionally substituted by one or more halogen atoms; C1-C4 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy; and C(O)OC1-C6 alkyl, wherein the aryl and heterocyclyl substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.
In an embodiment of the invention as described anywhere herein, wherein
Z is independently OH, C1-C4 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, NR19R21, C(O)OR19, C(O)R19, SR19, OR19, CN, NO2, or halogen;
R19 and R21 are each independently H; C1-C4 alkyl; C3-C6 cycloalkyl; or C1-C4 alkoxy-C1-C4 alkyl, wherein all alkyls are optionally substituted with halogens.
In an embodiment of the invention as described anywhere herein, wherein
Z is independently OH, C1-C4 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, C(O)OR19, C(O)R19, OR19, CN, or halogen;
R19 is H; C1-C4 alkyl; C3-C6 cycloalkyl; or C1-C4 alkoxy-C1-C4 alkyl, wherein all alkyl are optionally substituted with halogens.
In an embodiment of the invention as described anywhere herein, wherein
Z is independently, C1-C4 alkyl optionally substituted by one or more halogen atoms, C1-C4 alkoxy or halogen;
It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments. It is understood by those skilled in the art that combinations of substituents where not possible are not an aspect of the present invention.
Another embodiment of the invention as defined above provides compounds according to Formula I and Formula II, represented by    7-(2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)heptanoic acid;    7-(2,3-bis(4-fluorophenyl)-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid;    7-(2,3-d-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid;    7-(2,3-bis(4-methoxyphenyl)-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid;    6-(2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)hexanoic acid;    5-(2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)pentanoic acid;    7-(6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoic acid;    Ethyl 7-(6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoate;    rac-6-(1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexanoic acid;    Enantiomer 1 of 7-(2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoic acid;    Enantiomer 2 of 7-(1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)heptanoic acid;    2-(3-((6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)methyl)phenoxy)acetic acid;    Ethyl 2-(3-((6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)methyl)phenoxy)acetate;    Enantiomer 2 of 7-(2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoic acid;    Enantiomer 1 and Enantiomer 2 of 6-(1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexanoic acid;    6-(6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)hexanoic acid; and    Enantiomer 1 of 7-(1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)heptanoic acid.
Especially preferred specific compounds of Formula I, Ia, II or IIa or pharmaceutical salts thereof are those described hereinafter in the Examples.